Therapeutic Hypothermia for Newborns

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Transcript of Therapeutic Hypothermia for Newborns

SummaryDELAYOVERCOOLHYPERTHERMIAHYPOCARBIADon’t forget THE COOL HIP HIPPO!!!Does it work? - Yes, but it is no panaceaIs it safe? - Yes, under protocols with modest hypothermiaWho should be cooled? - Newborns who meet criteria for moderate -severe encephalopathy.Historical PerspectivesYoung S. Byun MD, FAAPPediatrix/Mednax, Dept of NeonatologyWinnie Palmer Hospital for Women & BabiesDisclosuresRelevant financial relationshipsNothing to discloseHephaestusObladen M., Lame from birth: early concepts of cerebral palsy. J Child Neurol, 2011, 26: 248PanSatanPainting by Mantegna 1465for Newborns with Hypoxic Ischemic EncephalopathyDeformations have been attributed to supernatural causes since ancient times4,000 year old Sumerian, Chaldean, and Babylonian incantations against the evil eye were translated from cuneiform writings. Pregnant women and neonates were believed to be particularly vulnerable and mothers hid their babies from the gaze of strangers and tried to protect themselves with amulets.Do you know?

□ □ □ □ □ □ □ □ □ □ □ □Moderate or Severe Encephalopathy (Must have at least one finding in 3 of 6 categories)CategoryModerate HIESevere HIELevel of ConsciousnessLethargic or ObtundedStupor or ComaSpontaneous ActivityDecreased ActivityNo activityPostureDistal flexion w/ complete extension, usually enhanced by stimulationDecerebrate posturingToneHypotonicFlaccidPrimitive ReflexesWeak suck or incomplete moro or strong asymmetric tonic neck reflexAbsent suck or moroAutonomic systemMiosis or bradycardia or irregular breathing patternVariable/Unequal/absent light reflexes or ApneaBeware! THE COOL HIP HIPPO!!!MiniMuffs - Neonatal Noise Attenuators by Natus MedicalDifferent Populations1) Preterm HIE (recruiting). Vanderbilt University. Babies 32-36 weeks with HIE. Coolcap x72 hrs. f/u at 6, 12 and 24 months.2) CoolNEC (recruiting) Great Ormond St Hospital UK. Controlled hypothermia to 33.5C for 48 hours to reduce the severity of critical illness in neonates with severe necrotizing enterocolitis.Cooling Followup Studies1) TOBY Children Study (enrolling). Imperial College London. Study children 6-7 years of age over 3 years, who were in TOBY. IQ >84, the presence and severity of disabilities, educational attainment and the economic impact on families and service providers.2) CoolCap followup Study (enrolling). University of Rochester. Phone interview 7-8 years of age.3) NICHD (published in NEJM, May 31, 2012). Death or IQ <70 in 47% cooled vs. 62% control (p=0.06). Death 28% vs. 44% (p=0.04). Death or severe disability 41% vs. 60% (p=0.03).Combination Therapies1) TOBYXe (not yet recruiting). Imperial College London. Randomized to treatment with hypothermia only or hypothermia and 30% xenon for 24 hours. MRS and MRI at 4-10 days.2) CoolXenon2 (not yet recruiting). United Bristol Healthcare. Randomized to 72 hours WBC or 72h cooling +18hr 50% Xenon. aEEG and MRI <2 weeks.3) DANCE (not yet recruiting). University of Utah. Darbepoetin alfa (Darbe), a recombinant human erythropoietin (EPO)-derived molecule, has an extended circulating half life and comparable biological activity to EPO. The proposed study is a Phase I/II dose safety and pharmacokinetic trial of early Darbe administered with hypothermia in newborn infants with moderate to severe birth asphyxia. 4) Topiramate with hypothermia (recruiting). NeoNATI - Azienda Ospedaliero, Universitaria Meyer. Topiramate has been demonstrated to posses neuroprotective properties against hypoxic ischemic brain damage, both in vitro and in animal models, and has been shown to be safe in asphyxiated newborns. TPM 10 mg/kg once a day will be administered with an orogastric tube as enteric-coated granules mixed with water on arrival in the NICU, when the cooling will be begun (T0), once a day for the first 3 days of life, for a total of 3 doses per patient.Biomarkers1) NEOCORD (recruiting). Assistance publique Hopitaux De Marseille. Study cord blood stem cells from babies with HIE vs. healthy newborns.2) MARBLE (recruiting). University College London. (1) To establish normative ranges for thalamic 1H MRS NAA concentration and Lac/NAA in healthy newborn infants (2) To examine the accuracies of thalamic 1H MRS NAA concentration and Lac/NAA for predicting adverse neurodevelopmental outcome in HIEModifying Hypothermia1) Optimizing Cooling Trial (recruiting). NICHD 19 centers. (1) cooling for 72 hours to 33.5°C (2) cooling for 120 hours to 33.5°C (3) cooling for 72 hours to 32.0°C (4) cooling for 120 hours to 32.0°C. Evaluate whether whole-body cooling (WBC) initiated at <6 hours of age and continued for 120 hours and/or a depth at 32.0°C will reduce death and disability at 18-22 months corrected age.2) Phase Changing Material (Ongoing). UK. examine the efficacy of phase changing material in providing satisfactory therapeutic hypothermia in neonatal encephalopathy, in a mid resource setting.3) Late Hypothermia for HIE (recruiting). NICHD 22 Centers. Evaluate whether WBC initiated between 6-24 hours of age and continued for 96 hours in infants ≥ 36 weeks with HIE will reduce the incidence of death or disability at 18-24 months of age. Will enroll 168 infants with signs of HIE and randomly assign them to either hypothermia or a non-cooled control group.Future DirectionsRutherford M, Malamateniou C, McGuinness A., et al., Magnetic resonance imaging in hypxic-ischaemic encephalopathy. Early Human Development. Vol 86; Issue 6, June 2010, p. 351-360.T1 weighted images showing focal regions of abnormal high signal intensity. The severity of basal ganglia and thalamic injury can be graded into mild (a) moderate (b) and severe (c). There is already atrophy of the basal ganglia and thalami with flattening of the border of the lateral lentiform nucleus in the neonate with severe lesions. Cortical and subcortical white matter lesions T1 weighted images level of the central sulcus (a, c) and ADC map (b). At 3 days there is minimal highlighting of the cortex of the central sulcus on conventional images (a) but marked restriction of diffusion with low signal intensity on the ADC map (b). By day 14 there is overt cortical highlighting and abnormal low signal intensity in the adjacent subcortical white matter. (c) This pattern of injury is usually present in neonates with moderate and severe basal ganglia lesions.T2The posterior limb of the internal capsule. T1 weighted images (top row) with T2 weighted images (bottom row). (a) Normal appearances of the posterior limb of the internal capsule (PLIC) (arrows). (b, c, d) Abnormal appearances of paired T1 and T2 weighted sequences in three different infants with HIE. It is important to use both T1 and T2 weighted sequences to assess the PLIC.T1T2DWIDay 2Day 15Top row: There is loss of anatomical detail throughout the brain on the T1 weighted image but the changes are quite subtle. There is some white matter high signal intensity on the T2 weighted image. The DWI shows linear areas of increased signal intensity mainly in the cortex but no larger focal lesions of altered signal intensity. However on an apparent diffusion coefficient (ADC) map all regions of the brain showed marked reduction in ADC. Values are shown with normal average value in brackets. Bottom row. At 15 days there has been widespread infarction throughout the hemispheres with abnormal signal intensity and some atrophy of the BGT seen on both T1 (left) and T2 weighted (right) images.MR spectroscopy can detect metabolites such as lactate, N-acetyl aspartate, choline, and creatine that provide functional data regarding metabolic integrity in specific regions of the brain.When the brain becomes ischemic, it switches to anaerobic glycolysis and lactate accumulates. Markedly elevated lactate is the key spectroscopic feature of cerebral hypoxia and ischemia. Choline is elevated, and NAA and creatine are reduced. If cerebral infarction ensues, lipids increase.NICHD Neonatal Research Network. Both minimum PCO(2) and cumulative PCO(2) <35 mm Hg were associated with poor outcome (P < .05). Moreover, death/disability increased with greater cumulative exposure to PCO(2) <35 mm Hg.

The basal ganglia/thalamus pattern was associated with the most impaired motor and cognitive outcome at 30 months.

Miller et al., Patterns of brain injury in term neonatal encephalopathy. (J Pediatr 2005;146:453-60)Cerebral palsy was associated with God's wrath, witchcraft, the evil eye, or maternal imagination. In the Middle Ages, the midwife's negligence or difficult teething was held responsible.‘‘The devil replaces legitimate children with changelings and killcrops to plague mankind. He often pulls certain girls into the water, impregnates them, and keeps them with him until they deliver their children; he then places those children in cradles, taking the legitimate children away.’’ Martin Luther’s proposal to drown these infants was later resumed by Werner Catel, a Leipzig pediatrician who helped organize the murder of handicapped children in Nazi Germany.